4pvf

Crystal structure of Homo sapiens holo serine hydroxymethyltransferase 2 (mitochondrial) (SHMT2), isoform 3, transcript variant 5, 483 aa, at 2.6 ang. resolution

spinqualitylabelsall models 4pvf, resolution 2.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4pvf is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.6Å Ligands: GOL, LLP, PEG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function GLYM_HUMAN Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Required to prevent uracil accumulation in mtDNA. Interconversion of serine and glycine. Associates with mitochondrial DNA. Publication Abstract from PubMed Adaptive metabolic reprogramming gives cancer cells a proliferative advantage. Tumour cells extensively use glycolysis to sustain anabolism and produce serine, which not only refuels the one-carbon units necessary for the synthesis of nucleotide precursors and for DNA methylation, but also affects the cellular redox homeostasis. Given its central role in serine metabolism, serine hydroxymethyltransferase (SHMT), a pyridoxal 5'-phosphate (PLP)-dependent enzyme, is an attractive target for tumour chemotherapy. In humans, the cytosolic isoform (SHMT1) and the mitochondrial isoform (SHMT2) have distinct cellular roles, but high sequence identity and comparable catalytic properties, which may complicate development of successful therapeutic strategies. Here we investigated how binding of the cofactor PLP controls the oligomeric state of the human isoforms. The fact that eukaryotic SHMTs are tetrameric proteins while bacterial SHMTs function as dimers may suggest that the quaternary assembly in eukaryotes provides an advantage to fine-tune SHMT function and differentially regulate intertwined metabolic fluxes, and may provide a tool to address the specificity problem. We determined the crystal structure of SHMT2, and compared it to the apo-enzyme structure, showing that PLP binding triggers a disorder-to-order transition accompanied by a large rigid-body movement of the two cofactor-binding domains. Moreover, we demonstrated that SHMT1 exists in solution as a tetramer, both in the absence and presence of PLP, while SHMT2 undergoes a dimer-to-tetramer transition upon PLP binding. These findings indicate an unexpected structural difference between the two human SHMT isoforms, which opens new perspectives for understanding their differing behaviours, roles or regulation mechanisms in response to PLP availability in vivo. How pyridoxal 5'-phosphate differentially regulates human cytosolic and mitochondrial serine hydroxymethyltransferase oligomeric state.,Giardina G, Brunotti P, Fiascarelli A, Cicalini A, Costa MG, Buckle AM, di Salvo ML, Giorgi A, Marani M, Paone A, Rinaldo S, Paiardini A, Contestabile R, Cutruzzola F FEBS J. 2015 Jan 24. doi: 10.1111/febs.13211. PMID:25619277 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Serine hydroxymethyltransferase 3D structures

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